BCL6 is the most commonly involved oncogene in B-cell lymphomas, and is expressed constitutively in a majority of patients with the two most frequent forms of lymphoma: the diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma (FL). Many of these BCL6 positive tumors require the continued presence of BCL6 in order to maintain their survival. BCL6, a member of the BTB/POZ family of transcriptional repressors, mediates its effects on gene silencing through recruitment of the SMRT, N- CoR and BCoR corepressor proteins. The BTB domain of BCL6 provides an extended groove-like surface to which a linear peptide from the SMRT, N-CoR and BCoR corepressor can bind with high affinity. This protein-protein interaction is required for BCL6 to repress critical checkpoint regulatory genes such as ATR and TP53. We hypothesize that drugs designed to occlude the BCL6 BTB domain corepressor binding groove will block the ability of BCL6 to repress its critical target genes and force lymphoma cells to undergo programmed cell death. This proposal brings together expertise in computer-aided drug design, medicinal chemistry, structural biology and lymphoma biology to identify and optimize low molecular weight chemical compounds that disrupt the ability of BCL6 to recruit corepressors through the BTB lateral groove and determine the therapeutic efficacy of BCL6 small molecule inhibitors in B-cell lymphomas in vitro and in vivo. In preliminary data this team has already demonstrated the ability to generate specific BCL6 inhibitors that are able to block BCL6 activities and kill DLBCLs in vitro and in vivo. The proposed methodology will build on this success by performing more advanced forms of computer aided drug design, and using functional and structural information obtained through multiple methods. The expected outcome is the development of several chemical structures with nanomolar affinity for BCL6, favorable drug-like properties and potent therapeutic efficacy.